JP2015518900A - Compounds for treating inflammation and pain - Google Patents

Abstract

The present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide. The present invention also provides inflammation or inflammation by administering ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof. It is also directed to methods for treating related disorders and pain.

Description

FIELD OF THE INVENTION The present invention relates to a medicament comprising a pharmaceutically acceptable carrier and an active compound of ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, or a pharmaceutically acceptable salt thereof. Relates to the composition. The invention also relates to methods of using said compounds for treating inflammation or inflammation-related disorders and pain.

BACKGROUND OF THE INVENTION Inflammation is a phenomenon in which microbial or tissue damage intensifies enhanced vascular permeability, upregulation of endothelial receptors, and surrounding tissues, and strongly enhances the conventional situation of inflammation: redness, swelling, fever and pain. A step of inducing the release of cytokines and chemokines from various cell types that generate an increased release of that of various cells of the innate and adaptive immune systems that are generated.

  Inflammation is a localized response of living tissue due to damage that can be caused by a variety of intrinsic and extrinsic factors. Exogenous factors include physical, chemical and biological factors. Endogenous factors include inflammatory mediators, antigens and antibodies. Intrinsic factors often progress under the influence of extrinsic damage. The inflammatory response is often followed by altered structure and permeability of the cell membrane. Endogenous factors, ie mediators, antigens and autogens, define the nature and type of the inflammatory response, especially its path in the area of injury. Acute inflammation progresses when tissue damage is limited to the creation of mediators. If the immune response is also involved in the process through the interaction of antigen, antibody and autoantigen, a long-term inflammatory process will proceed. Various exogenous agents such as infection, trauma, radiation also provide the course of the inflammatory process at the molecular level by the damaging cell membranes that initiate biochemical reactions.

  Based on physical causes, pain can be divided into three types: nociceptive, neuropathic, and mixed types.

  Nociceptive pain is the term for pain detected by specialized sensory nerves called nociceptors. These nerves are located in soft tissues, such as muscle and skin, and whole internal organs. There are two types of nociceptive pain: somatic pain and visceral pain. Visceral pain originates from internal organs. Deep somatic pain is initiated by nociceptor stimulation in ligaments, tendons, bones, blood vessels, fascia and muscles, and is dull, tingling, incomplete localized pain. Examples include sprains and fractures. Superficial pain is initiated by the activation of nociceptors in the skin or other surface tissues and is sharp, clear and well located. Examples of trauma that produces superficial somatic pain include minor wounds and minor (primary) burns. Nociceptive pain is usually short in duration and terminates when the injury is restored. Examples of nociceptive pain include post-operative pain, benign drugs, fractures, burns, bumps, bruises and inflammatory pain.

  Neuropathic pain is pain caused by an injury or disease that affects the somatosensory system. Neuropathic pain results from spontaneous ectopic neuron release in either the central or peripheral nervous system. Most neuropathic pain is chronic pain because the underlying etiology is irreversible. Most people describe neuropathic pain, such as throbbing pain, burns, tingling, stinging pain, electroshock pain, numbness and permanent allodynia. The nomenclature for neuropathic pain is based on the etiology and location of the initiating nervous system, such as central pain after stroke, diabetic peripheral neuropathy, postherpetic (or postherpetic) neuralgia, end-stage cancer pain, limb pain .

  Mixed types of pain are characterized by the coexistence of both nociceptive and neuropathic pain. For example, muscle pain induces central or peripheral nerve sensitization leading to chronic low back pain, migraine and fascial pain.

  Connective tissue is subject to constant and continuous stress and trauma. Acute or chronic effects and the natural progression of various degenerative diseases all produce painful inflammation of joint parts such as the neck, back, arms, hips, ankles and feet. Their pain is common and often debilitating.

  Current treatments are directed at some or all pathogenic components of inflammation. For example, corticosteroids have a wide range of activities, and NSAISA is more particularly an anti-prostaglandin and analgesic. All current treatments have a relatively high rate of side effects, and side effects are severe and severe.

  There is a need for compositions and methods for treating inflammation, inflammation-related diseases, pain. The composition should be economical and easy to manufacture, and the method should be effective and should not have severe side effects.

SUMMARY OF THE INVENTION The present invention provides a pharmaceutically acceptable carrier and an active compound of ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, or a pharmaceutically acceptable salt or solvate thereof. Directed to a pharmaceutical composition comprising. The compound is preferably at least 90% dull (w / w).

  The present invention is also directed to methods for treating inflammation, inflammation-related disorders and pain. The present invention comprises administering ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide or a pharmaceutically acceptable salt thereof to a subject in need thereof. The pharmaceutical composition comprising the active compound may be applied in any acceptable mode of administration, including topical, oral and parenteral (eg, intravenous, intramuscular, subcutaneous or rectal). Topical administration and oral administration are preferred.

Detailed Description of the Invention Definitions “Alkyl” means a straight or branched chain of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. Mention the group.
“Arylalkyl” refers to an aryl-alkyl-group having from 1 to 6 carbon atoms in the alkyl portion and from 6 to 10 carbon atoms in the aryl portion. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
“Cycloalkyl” refers to a cyclic alkyl group of 3 to 12 carbon atoms having a single ring or multiple condensed rings optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups are, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like Or a plurality of ring structures such as adamantyl and the like.

“Pharmaceutically acceptable salt” as used herein is a salt that retains the desired biological activity of the invention and does not impart undesired toxic effects. Pharmaceutically acceptable salts include crystalline polymorphs and amorphous forms of different salts. Pharmaceutically acceptable salts can be formed with metals or organic counterions and include, but are not limited to: alkali metal salts, such as sodium or potassium salts: alkaline earth metals Salts, such as magnesium or calcium salts; and ammonium or tetraalkylammonium salts, ie NX ₄ + (where X is C _1-4 ).

  A “solvate” as used herein is an addition complex that is combined in a certain proportion with a co-solvent in which the compound is acceptable. Co-solvents include, but are not limited to: ethyl acetate, lauryl lactate, lactic acid, myristyl, cetyl lactate, isopropyl myristate, methanol, ethanol, 1-propanol, isopropanol, 1-butanol , Isobutanol, tert-butanol, acetone, methyl ethyl ketone, acetonitrile, benzene, toluene, xylene, ethylene glycol, dichloromethane, 1,2-dichloroethane, N-methylformamide, N, N-dimethylformamide, N-methylacetamide, pyridine, Dioxane and diethyl ether.

（式中、
Ｒ₁及びＲ₂は、独立してＨ、直鎖アルキル、分枝鎖アルキル、シクロアルキル及びアリールアルキルであり、
ｎ１＝２−１２であり、
ｎ２＝１−１１である）
で表される、ω−（メチルスルホニル）アルキルアミン（式Ｉ）又はω−（メチルスルホニル）アルキルアミド（式II）、又は医薬的に許容されるその塩又は溶媒和物が、炎症、炎症−関連障害、及び疼痛を治療するために有効であることを発見した。 ω- (Methylsulfonyl) alkylamine and ω- (methylsulfonyl) alkylamide The inventors have the following formula I or formula II:

(Where
R ₁ and R ₂ are independently H, straight chain alkyl, branched chain alkyl, cycloalkyl and arylalkyl;
n1 = 2-12,
n2 = 1-11)
Ω- (methylsulfonyl) alkylamine (formula I) or ω- (methylsulfonyl) alkylamide (formula II), or a pharmaceutically acceptable salt or solvate thereof, is represented by inflammation, inflammation- It has been found effective for treating related disorders and pain.

Preferred ω- (methylsulfonyl) alkylamines and ω- (methylsulfonyl) alkylamides useful for the present invention are compounds having the following formulas Ia and IIa (R ₁ and R ₂ are H) or pharmaceuticals Or its pharmaceutically acceptable salt or solvate:

Some preferred compounds are 3- (methylsulfonyl) propylamine (molecular weight = 137.05, A), 3- (methylsulfonyl) propionamide (molecular weight = 151.93, B) and are shown below:

  A series of ω- (methylsulfonyl) alkylamines can be prepared by reducing the corresponding ω- (methylsulfonyl) alkylnitrile with borane-dimethylsulfide or other suitable reducing agent. On the other hand, they alkylate sodium thiomethoxide or sodium methanesulfinate with the corresponding N- (ω-haloalkyl) phthalimide, followed by peroxide (eg OXONE®) or other It can be prepared by oxidation with a suitable oxidant and / or subsequent hydrazine degradation.

  A series of ω- (methylsulfonyl) alkylamides can be prepared by subjecting its corresponding ω- (methylsulfonyl) alkylnitrile to conditions for acid or base hydrolysis. On the other hand, they can be prepared from its corresponding carboxylic acid / carboxylic acid derivative using established synthetic methods.

Pharmaceutical composition The present invention relates to one or more pharmaceutically acceptable carriers and active compounds ω- (methylsulfonyl) alkylamines or ω- (methylsulfonyl) alkylamides, or pharmaceutically acceptable salts thereof. Alternatively, a pharmaceutical composition comprising a solvate is provided. The active compound or pharmaceutically acceptable salt or solvate thereof in a pharmaceutical composition is generally about 0.01-20%, or 0.05-20%, or 0 for topical formulations. 1-20%, or 0.2-15%, or 0.5-10%, or 1-5% (w / w); for injectable formulations, about 0.1-5%; patch It is present in an amount of 0.1-5% for the formulation; about 1-90% for the tablet formulation; and 1-100% for the capsule formulation.

  According to one embodiment, the active compound can stabilize any acceptable carrier, such as a cream, gel, lotion, or active compound, and deliver it to the area affected by topical application. Incorporated into other types of suspensions. According to another embodiment, the pharmaceutical composition can be present in a dosage form such as a tablet, capsule, granule, fine granule, powder, syrup, suppository, injectable solution, patch, or the like. The pharmaceutical composition can be prepared by conventional methods.

  Pharmaceutically acceptable carriers that are inert ingredients can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous base solutions, suspensions, emulsions, microemulsions, micelle solutions, gels and ointments. Pharmaceutically acceptable carriers can also include ingredients including but not limited to: saline and aqueous electrolyte solutions; ionic and non-ionic penetrants, For example, sodium chloride, potassium chloride, glycerin, and dextrose; pH adjusters and buffers such as hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as bisulfite; Sulfites, metabisulfites, thiosulfuric acid, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and salts of ascorbyl palmitate, acids and / or bases; surfactants such as Lecithin, phospholipid, phosphatidylcholine, phosphatidylethanol And phosphatidylinositol (but not limited to); poloxamers and poloxamines, polysorbates such as polysorbate 80, polysorbate 60, polysorbate 20, polyethers such as polyethylene glycol and polypropylene glycol; polyvinyl such as polyvinyl alcohol and povidone; cellulose Derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats and oils such as lanolin, peanut oil, palm oil, soybean oil; mono-, Di- and triglycerides; polymers of acrylic acid, such as carboxypolymethylene gels, and Hydrophobically modified crosslinked acrylic copolymers; polysaccharides such as dextran and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers can be preserved against bacterial contamination using well known preservatives, such as benzalkonium chloride, ethylenediaminetetraacetic acid, and salts thereof, benzethonium chloride , Chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, but are not limited thereto or may be formulated as a non-preservative formulation for single or multiple use.

  For example, tablet formulations or capsule formulations of such active compounds can contain other excipients that are bioactive and have no reaction with the active compound. Excipients in tablets can include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate modifiers. The binder promotes adhesion of the formulation particles and is important for tablet formulations. Examples of binders include but are not limited to: carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, karaya gum, starch, starch, and tragacanth gum, poly (acrylic acid), And polyvinylpyrrolidone.

  For example, such active compound patch formulations contain several inactive ingredients such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D-sorbitol, gelatin, kaolin, methyl paraben, polysorbate 80, povidone , Propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. The patch formulation can also include a skin permeability enhancer, such as lactate ester (eg, lactyl lactate) or diethylene glycol monoethyl ether.

  Topical formulations containing such active compounds can exist in the form of gels, creams, lotions, liquids, emulsions, ointments, sprays, solutions, and suspensions. Inactive ingredients in topical formulations include, for example, but are not limited to: Urillac (emollient / permeation enhancer), diethylene glycol monoethyl ether (emollient / permeation enhancer), DMSO (solubility enhancer) ), Silicone elastomer (rheology / texture modifier), caprylic acid / capric acid triglyceride, (emollient), octisalate, (emollient / UV filter), silicone oil (emollient / diluent), squalene (emollient) , Sunflower oil (emollient), and silicon dioxide (thickener).

  According to one embodiment, lauryl lactate (eg, about 0.1-10%, or about 0.2-5%, or about 0.5-5%) is included in the topical gel formulation. Lauryl lactate appears to be safe for topical administration. Lauryl lactate is eligible for human use in medicine and cosmetics. Lauryl lactate enhances the permeability of the compound when used in topical formulations. Preferably, lauryl lactate is purified to achieve a purity of 90% or higher, preferably 95% or higher; high purity mitigates the presence of hydrolysis and oxidizing agents. Furthermore, DMSO at 0.1-20%, or 0.5-10% (w / w) in the formulation provides adequate solubility of such active compounds.

  According to another embodiment, diethylene glycol monoethyl ether is included in the topical gel formulation.

Usage Inflammation is a process and condition of histopathology that results from the activation and continuation of the innate and acquired components of the immune system. Arachidonic acid cascades and cytokine production and action in cell-to-cell interactions are critical components of immune activation and response, which induces inflammation. Arachidonic acid is present in many cell membranes. When arachidonic acid is excised from the membrane, it can produce many of the known eicosanoids, such as prostaglandins and leukotrienes, known as pro-inflammatory entities.

  The active compounds are effective in inhibiting the release of pro-inflammatory cytokines (eg IL-1β, IL-6, TNFα, IL-4 and IFNγ) from human peripheral blood mononuclear cells in vitro. The active compounds, when applied topically, are anti-inflammatory in a mouse ear swelling model where inflammation is induced by arachidonic acid.

  The present invention is also directed to a method of treating inflammation and / or pain. The active compound, ie ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, preferably 3- (methylsulfonyl) propylami or 3- (methylsulfonyl) propionamide, can be used as is or Furthermore, it can be administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The method comprises initially identifying a subject having inflammation and / or pain and administering to the subject an active compound in an amount effective to treat inflammation and / or pain. An “effective amount”, as used herein, is an amount effective to treat a disease by ameliorating a pathological condition or alleviating the symptoms of the disease.

  According to one embodiment, the method reduces or reduces symptoms associated with inflammation. The present invention provides a method for treating local symptoms of inflammation characterized by acute or chronic swelling, pain, redness, elevated body temperature, or in some cases, loss of function.

  According to another embodiment, the present invention provides a method of reducing pain symptoms regardless of the cause of the pain. The general term “pain” that can be treated by the methods of the present invention encompasses nociceptive, neuropathic and mixed types. The present invention reduces a variety of severe pain, ie, mild, moderate and severe pain; acute and chronic pain. The present invention is effective in the treatment of joint pain, muscle pain, tendon pain, burn pain and pain caused by inflammation, such as rheumatoid arthritis.

  According to one embodiment, the present invention is useful for the treatment of inflammation and / or pain associated with the musculoskeletal system or skin. Highly innervated musculoskeletal and dermal systems have a high capacity for pain demonstration. Furthermore, the musculoskeletal system has a high capacity for tissue swelling and the skin has a high capacity for redness, swelling and fever. In the musculoskeletal and skin systems, the degree of tissue damage is often magnified in proportion to the resulting inflammatory response. In the skin, just firm stroking will cause the release of cytokines, IL-1 and TNF.

  The present invention provides methods for treating inflammation and / or pain associated with inflammatory skeletal or muscular diseases or conditions. The method comprises identifying the subject in need thereof and administering to the subject the compound in an amount effective to treat inflammation and / or pain. Skeletal or muscular diseases or conditions include musculoskeletal sprains, musculoskeletal strains, tendonopathy, peripheral nerve root disorders, osteoarthritis, degenerative joint diseases, polymyalgia rheumatic, juvenile arthritis, gout, ankylosing Spondylitis, psoriatic arthritis, systemic lupus erythematosus, chondritis, tendonitis, bursitis, eg common lateral epicondylitis (tennis elbow), medial epicondylitis (pitcher elbow) and trochanteric bursitis , Temporomandibular joint syndrome, and fibromyalgia.

  The present invention provides a method for treating inflammatory skin diseases such as inflammation and / or pain associated with dermatitis, psoriasis, and acne. The method comprises identifying the subject in need thereof and administering to the subject the compound in an amount effective to treat inflammation and / or pain.

  The present invention further provides a method for treating inflammation and / or pain associated with inflammatory skin diseases such as dermatitis, psoriasis, and acne (acne vulgaris). The method comprises identifying the subject in need thereof and administering to the subject the compound in an amount effective to treat inflammation and / or pain.

  The skin is highly responsive to environmental stimuli, and the keratinocyte epidermal component is a very rich source of arachidonic acid and both IL-1 and TNF pro-inflammatory cytokines. Langerhans cells, skin dendritic cells, recognize and process antigens for further immune responses of various lymphocytes, and all of those cells are mediated through their specific cell surface receptors. It is mainly regulated by cytokines.

  Dermatitis (also called eczema) is a common inflammation of the skin. Specific types of dermatitis include atopy, contact, money, and light-induced.

  Contact dermatitis is a subsequent exposure of the skin to a sensitized allergen, with irritating exposure to the skin without a specific adaptive immunological etiology, or with allergic sensitization and a specific adaptive immunological etiology Any of the inflammatory conditions of the skin. Both initiate disease through cell-to-cell messaging with eicosanoid and / or cytokine moieties produced by epithelial cells, macrophages, dendritic cells, neutrophils, and various T and B lymphocytes, and Includes innate and acquired immune system responses, including arachidonic acid and cytokine components, that propagate. Contact dermatitis can be either acute or chronic. The acute form is pruritus with erythema, edema, and micro or macro vesicularization in the area of skin contact by the initiation factor. The chronic form is pruritus with mild erythema and especially cracks on the hands.

  Atopic dermatitis is a genetically determined disease that is part of the broad disease complex of atopy, including asthma, hay fever and atopic dermatitis. Many individuals with atopic dermatitis have various mutations in the filaggrin gene that, when poor, encodes an important skin structural protein that results in an abnormal barrier function of the epidermis. The altered barrier initiates an innate immune response, including arachidonic acid and eicosanoids, and an acute response of itching, erythema and subsequent scratches, and further includes inflammation primarily by TH2-induced and active lymphocytes Allows exposure to multiple environmental allergens that are initially recognized by the recruitment of eosinophils, mast cells and other inflammatory cells that activate the adaptive immune response. Atopic dermatitis responds to many cytokine inhibitors, such as cyclosporine and tacrolimus.

  The current theory of psoriasis etiology is that in individuals who are genetically sensitive, triggering events in the epidermis, such as trauma or superantigen contact, are related to the innate immune system by arachidonic acid and eicosanoid production, mobilization and neutrophil activity. To initiate a response. Subsequent conversion of said response to a response to TH1-adaptive immunity by cytokine activation and activity of specific T lymphocytes results in pathological changes in the epidermis and dermis, which are erythematous, thickened and scaly Leading to typical psoriasis lesions. Psoriasis responds to a host of various immune modulators such as cyclosporine, methotrexate, and certain biologics that interfere with cytokine signaling.

  Acne vulgaris, a progressive inflammatory disease of the sebaceous follicular unit of the face and upper breast and back, in particular, is very common in men and women after puberty, and even in women, even before adrenal maturation Is a common disease. Increased production of androgen hormone by the adrenal gland, ovary and testicular gland, and the pilosebaceous unit itself results in an increase in sebum and a change in its lipid composition, which leads to an early lesion of acne, the follicular sebaceous follicle Infrared—combines with follicular sebaceous epithelial cells to cause some blockage of the funnel portion. The resulting dilated and adolescent sebum segregates leak through the follicles into the dermis and degrade triglycerides in sebum into free fatty acids that initiate the arachidonic acid pathway of eicosanoid formation and subsequent inflammation. Promotes follicular colonization by Propionibacterium acnes, which produces enzymes for The fungus also initiates the action of continuing and amplifying chemokine production that attracts additional inflammatory cells to the area, and subsequent cytokine production and inflammation. Thus, the initiation and propagation of gradual inflammation in microcomedones generates progression to several characteristic lesions of inflammatory acne, papules, pustules, nodules, and cysts. The present invention includes general acne, acne acne, papulopustular acne, acne acne, nodular cyst acne, confluent acne, keloid acne on the nape of the neck, recurrent acne vulgaris Useful for treating necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, sun acne or acne medication.

  Rasha is a chronic symptom characterized by facial erythema and sometimes acne. The rosacea typically begins as redness on the middle of the cheek, nose or forehead, but also has little effect on the neck, chest, ears and scalp. In some cases, additional symptoms such as semi-permanent redness, telangiectasia (dilation of superficial blood vessels on the face), red dome-shaped papules (small bumps) and pustules, red eyes (rough eyes), Burns and tingling sensations, and in some cases, a red lobe nose (nasal nose) can progress. There are three types of rosacea that affect the skin: erythematous telangiectasia rosacea, papulopustular rosacea and aneurysmal rosacea.

  Ω- (Methylsulfonyl) alkylamines and ω- (methylsulfonyl) alkylamides that are effective in inhibiting arachidonic acid-induced inflammation and in impaired pro-inflammatory cytokine release are psoriasis, acne, rosacea And in the treatment of dermatitis, in particular inflammation and / or pain associated with contact dermatitis, atopic dermatitis and the like.

  Ω- (Methylsulfonyl) alkylamines and ω- (methylsulfonyl) alkylamides that are effective in inhibiting arachidonic acid-induced inflammation and in impaired pro-inflammatory cytokine release are useful for inflammatory skin diseases such as skin Effective in the treatment of inflammation (atopic dermatitis), psoriasis, acne and rosacea.

  ω- (methylsulfonyl) alkylamine and ω- (methylsulfonyl) alkylamide are selected from the group consisting of treatment of atopic dermatitis and erythema, induration, lichenification, scaling and exudation and scab Effective in alleviating one or more symptoms.

  Methanesulfonylalkylnitriles are effective in the treatment of psoriasis and in the relief of erythema, scaling, and / or psoriasis lesion thickness.

  Methanesulfonylalkylnitriles are effective in the treatment of acne and in the relief of acne lesions selected from the group consisting of closed facets, papules, pustules, nodules and cysts.

  ω- (methylsulfonyl) alkylamines and ω- (methylsulfonyl) alkylamides are used to treat rosacea and erythema, telangiectasia, red dome-shaped papules and pustules, red gritty eyes , And effective in alleviating one or more symptoms selected from the group consisting of burns and tingling sensations.

  The pharmaceutical composition of the present invention can be applied by local administration and systemic administration. Local administration includes topical administration. Systemic administration includes oral, parenteral (eg, intravenous, intramuscular, subcutaneous or rectal) and other systemic routes. In systemic administration, the active compound first reaches the plasma and then is dispersed in the target tissue. Topical administration and oral administration are the preferred routes of administration for the present invention.

Administration of the composition can vary based on the extent of injury and the individual response of each patient. For systemic administration, the plasma concentration of the active compound administered can vary; generally 1 × 10 ⁻¹⁰ −1 × 10 ⁻⁴ mol / l, and preferably 1 × 10 ⁻⁸ − 1 × 10 ⁻⁵ mol / l.

  According to one embodiment, the composition is applied topically over the affected area and rubbed into it. The composition is topically applied at least 1 or 2 times per day, or 3-4 times per day, depending on the pharmaceutical problem and the pathology of the disease that is chronic or acute. Generally, the topical composition is about 0.01-20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, or 0.5-10%, or Contains 1-5% (w / w) active compound. For example, topical compositions contain about 1 or 5% (w / w) of active compound. Depending on the size of the affected area, a topical composition of 0.2-85 ml, typically 0.2-10 ml, is applied to the individual per dose. The active compound passes through the skin and is delivered to the unpleasant site.

  According to one embodiment, the pharmaceutical composition is administered orally to the subject. The dosage for oral administration is generally 1-50, and preferably 1-5 mg / kg / day.

  According to one embodiment, the pharmaceutical composition is administered subcutaneously to the subject. The dosage for subcutaneous administration is generally 0.3-20, and preferably 0.3-3 mg / kg / day.

  One skilled in the art will appreciate that a wide variety of delivery mechanisms are also suitable for the present invention.

  The present invention is useful for the treatment of mammalian subjects such as humans, horses and dogs. The present invention is particularly useful in human therapy.

  The following examples further illustrate the invention. These examples are merely illustrative of the invention and do not limit the invention.

Example 1.3 Preparation of 3- (methylsulfonyl) propylamine hydrochloride 3- (methylsulfonyl) propionitrile was prepared from US patent application Ser. Nos. 13 / 324,777 or 61/603, which is incorporated herein by reference. , 744.

  Borane-dimethyl sulfide (20 mmol) was added dropwise to a solution of 3- (methylsulfonyl) propionitrile (10 mmol) in anhydrous tetrahydrofuran (50 ml) stirred at room temperature under nitrogen. The reaction mixture was then heated to 65-70 ° C. After 1 hour, the reaction was quenched by careful dropwise addition of methanol (50 ml) followed by 6N hydrochloric acid (10 ml). After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The solid residue was taken up in a boiling mixture of acetonitrile-ethanol (4: 1), filtered while hot and cooled to room temperature. Yield of 3- (methylsulfonyl) propylamine hydrochloride: 3.5 mmol, melting point: 146.9-147.4 ° C.

Example 2. Preparation of 3- (methylsulfonyl) propionamide 3- (methylsulfonyl) propionitrile was prepared from US patent application Ser. Nos. 13 / 324,777 or 61 / 603,744, which is incorporated herein by reference. Prepared according to the method described in the issue.

  3- (Methylsulfonyl) propionitrile (37 mmol) was partially added to cold concentrated sulfuric acid (10 ml). The reaction mixture was stirred at less than 5 ° C. for 0.5 hour and then at room temperature overnight. The reaction mixture was poured on ice and the pH was adjusted to about 7 by careful addition of 10N sodium hydroxide while maintaining the temperature below 5 ° C. The solution was concentrated under reduced pressure to give a white solid that was sonicated under methanol (200 ml) and then vacuum filtered. The filtrate was concentrated to a solid and then crystallized from hot ethanol. Yield of 3- (methylsulfonyl) propionamide: 30 mmol (purity of 98% or more according to gas chromatography).

Example 3 Anti-inflammatory activity of active compounds in mice by topical application 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide were prepared according to Examples 1 and 2 and used in this experiment.

  Test compounds, indomethacin (positive control) and vehicle were evaluated for anti-inflammatory activity in a topical arachidonic acid-induced ear swelling model in mice.

  Male ICR mice weighing 22 ± 2 g were used and randomly divided into 10 groups. Arachidonic acid (0.5 mg in 20 μl acetone: ethanol (1: 1)) was topically applied to the front and back of the right ear of each mouse. Test substances and vehicles as listed in Table 1 were applied in the same manner 30 minutes before and 15 minutes after application of aragidonic acid. The thickness of the right and left ears was measured and the difference was calculated as an indicator of inflammation in the right ear. Ear swelling was measured with a Dyer model micrometer gauge 60 and 90 minutes after arachidonic acid application as an indicator of inflammation. The percent inhibition was calculated according to the formula: Ic-It / Ic × 100, where Ic and It indicate the increase in ear thickness (mm) in control and treated mice, respectively. ANOVA and Dunnett tests were used to confirm significant differences between vehicle controls and treated groups. The results measured 60 minutes after arachidonic acid application are summarized in Table 1.

  All test compounds resulted in significant inhibition (30 and 42%) in arachidonic acid-induced ear swelling compared to the vehicle treated group. The difference between treated and vehicle-treated mice was determined to be statistically significant (p-value by t-test was less than 0.05).

Example 4 Gel preparation 1
Table 2 illustrates one gel formulation comprising ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide.

Example 5 FIG. Gel preparation 2
Table 3 illustrates one gel formulation comprising ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide.

Example 6 Inhibition of cytokine activity (predictive example)
Active compounds ω- (methylsulfonyl) alkylamines or ω- (methylsulfonyl) alkylamides were tested for their inhibitory effect on in vitro cytokine release from human peripheral fluid mononuclear cells (PBMC). Secretion of cytokines by PBMC plays a significant role in the inflammatory response.

  Each active compound is added in duplicate to a culture of fresh human PBM at 162 μM (22 μg / ml). One hour later, PBMCs are stimulated with mitogen lipopolysaccharide and concanavalin A (ConA) to secrete cytokines. Polysaccharides at 50 pg / ml are used to stimulate the release of interleukin IL-1β, IL-6 and tumor necrosis factor TNFα. ConA at 20 μg / ml is used to stimulate the release of IL-4 and ConA at 5 μg / ml is used to stimulate interferon IFNγ. The corticosteroid dexamethasone (100 nM) is used as a positive control. After 24 hours of incubation, the supernatant was assayed for cytokines using the Luminex Bead kit. The percent inhibition of IL-1β, IL-6, TNFα, IL-4 and IFNγ by the active compound and positive compound is calculated. The results show that the active compound has an inhibitory effect on cytokines involved in the inflammatory process.

Example 7 Systemic administration of drug product (predictive example)
This study is conducted to determine systemic (plasma) exposure of test substances after administration to rats by oral and subcutaneous routes.

  ω- (Methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide is prepared in water for oral administration and in saline for subcutaneous administration. Rats are used for this study. Male rats are dosed once at 50, 160 or 500 mg / kg by both oral and subcutaneous routes. Female rats (n = 2) are administered at 500 mg / kg only by both oral and subcutaneous routes. Blood is drawn from each rat at 0.25, 1, 2, 3, 4, 6, 12, 24 and 48 hours and measured for test substance concentration by LC / MS / MS.

  The average maximum plasma concentration (Cmax) measured after oral administration and after subcutaneous administration is determined. The above results show significant bioavailability of the test substance after both oral and subcutaneous routes.

Example 8 FIG. Anti-inflammatory activity of active compounds in mice by oral administration (predictive example)
Test compounds are suspended in vehicle (1% Tween 80 in water) to 5-15 mg / ml. Test compound, dexamethasone (positive control in vehicle), and vehicle are administered orally to mice and evaluated for anti-inflammatory activity in a topical arachidonic acid-induced ear swelling model in mice.

  Mice derived from male ICR weighing 22 ± 2 g are used for this experiment. 10-15 mice are used for each group (active compound, positive control, and vehicle). All animals are maintained in a controlled temperature (22-24 ° C.) and humidity (60% -70%) environment with a 12 hour light / dark cycle for at least 1 week prior to use.

  Arachidonic acid (0.5 mg in 20 μl acetone) is applied topically to the front and back of the right ear of the test animals to induce inflammation. Test compounds are administered orally by gavage in vehicle (10 ml / kg) and vehicle (10 ml / kg, 50-150 mg / kg) 1 hour prior to arachidonic acid exposure, while dexamethasone is administered 3% of arachidonic acid exposure. Orally before time. At 60 and 90 minutes after arachidonic acid induction of ear edema, the thickness of the right and left ears is measured and the difference is calculated as an indicator of inflammation in the right ear. Significant activity as a statistically significant inhibition in aragidonic acid-induced ear swelling (p-value determined by t-test was <0.05) versus vehicle-treated group Define.

Example 9 Anti-inflammatory and analgesic activity of active compounds in carrageenan model (predictive example)
An ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, is prepared according to Example 5 in a gel formulation.

  Test substances in gel formulations, ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, indomethacin (positive control), and vehicle (gel formulation without active compound) were induced by rat carrageenan. Evaluate for anti-inflammatory and analgesic activity in a limb inflammation model.

  Rats are used for this experiment. Carrageenan (0.1 ml of 1% suspension) is injected subcutaneously into the left hind limb to induce inflammation. Limb in test substance (1-5%) or vehicle gel in 0.05, 0.1, 0.15 or 2.0 ml volume at 1, 5, 2.5 and 3.5 hours following carrageenan administration. Apply topically. Indomethacin is orally administered at 5 mg / kg 1 hour after carrageenan administration. The degree of inflammation (edema or swelling) is determined using a plethysmograph and the limb volume is measured. Analgesia is determined by measuring limb escape to mechanical stimulation with von Frey filament. Inflammation and analgesia are measured 4 hours after carrageenan administration. The test substance is anti-antigen as measured by a significant decrease in limb volume and / or a significant increase, respectively, under the mechanical pressure required to induce limb escape compared to the vehicle control. -Measured to have inflammatory and / or analgesic properties.

Example 10 Analgesic activity of active compounds in hot plate model (prediction example)
An ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, is prepared into a gel formulation according to Example 5.

  Test substances: Gel formulations without active compound (1-5%), morphine (positive control) and vehicle (active compound) in the gel formulation are evaluated for analgesic activity in a rat hot plate.

  Rats are used for this experiment. Test substance gel (1-5%) or vehicle gel is topically applied to the limb in a volume of 0.05, 0.1, 0.15 or 2.0 mL. After 1 hour, the rat is placed on a 55 ° C. hot plate and the time to lick the paw is measured. Positive control morphine is administered orally at 30 mg / kg 1 hour prior to hot plate. The test substance is expected to have analgesic properties as measured by a significant increase in licking time compared to the vehicle control (t-test, p <0.05).

Example 11 Analgesic activity of active compounds in CFA-induced thermal hyperalgesia (predictive example)
CFA (complete Freund's adjuvant) is known to induce inflammatory pain (Walker, et al. JPET. 304: 56-62, 2003).

  Male Sprague-Dawley rats weighing 180 ± 20 g are used. Animals divided into groups of 8-10 each will receive a sub-injection (0.1 ml) of CFA (0.1% solution) in the hind limb to be tested 24 hours prior to the experiment. Thermal hyperalgesia is tested by using an IITC Model-336G (IITC INC. USA) device with a temperature-controlled glass bed set at 30 ° C. Each rat is placed in a plastic box on a glass floor. The light beam under the floor is aimed at the plantar surface of the right hind limb. Time is automatically measured when the limb is withdrawn from the thermal stimulus. The light intensity is adjusted by an average group reference latency (pre-CFA) of 12-14 seconds and an imposed 20 second cutoff latency. The withdrawal latency is obtained from each rat and defined as the thermal pain threshold. Twenty-four hours after CFA injection, rats are pre-selected for the experiment (showing a clear presence of thermal hyperalgesia) only if the latency to be withdrawn is 75% or less of baseline.

  An ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, is prepared according to Example 5 in a gel formulation. In gel formulation, active compound (1-5%), 1% Tween 80, active compound, morphine (positive control, oral, 20 mg / kg), topical vehicle (gel formulation without active compound), and oral Vehicle (in water, 1% Tween 80) is evaluated for analgesic activity in the formalin model.

  Test substance or vehicle was administered orally (20-60 mg / kg) or topical (1-5% gel formulation) 60 minutes before (after treatment) the level of thermal hyperalgesia was measured again on the plantar surface of the hind limb ,Administer. Calculate the mean limb escape time ± SEM. An unpaired student t-test is applied to compare post-treatment values between the test substance treated group and the vehicle control group. Positive activity is considered at P <0.05.

Example 12 Analgesic activity of active compounds in formalin test (predictive example)
The formalin test is a model of persistent pain due to formalin-induced tissue damage. The formalin model encompasses inflammatory, neurogenic and central mechanisms of nociception. The assay described below relates to the late inflammatory pain phase sensitive to both strong central and weak analgesic / anti-inflammatory agents (Hunskaar, et al., J. Neuroscience Meth. 14: 69- 76, 1985). The formalin test represents an appropriate model for testing compounds for treating neuropathic pain (Benson, et al. Proceedings of Measuring Behavior, 2008, Eds. Spink, et al, 324-325).

  An ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, is prepared according to Example 5 in a gel formulation. In gel formulation, active compound (1-5%), 1% Tween 80, active compound, morphine (positive control, oral, 30 mg / kg), topical vehicle (gel formulation without active compound), and oral Vehicle (in water, 1% Tween 80) is evaluated for analgesic activity in the formalin model.

  The test substance is applied to a group of 8-10 CD-1 derived male mice weighing 23 ± 3 g, 1 hour before the plantar injection of formalin (0.02 ml, 2% solution). . Test substances are administered orally (20-60 mg / kg) or topically (1-5% gel formulation) to the plantar surface of the hind limbs. More than 50% reduction in the induced hindlimb licking time recorded for the next 10-30 minutes indicates analgesic activity. Positive activity is expected to be a significant increase in time to lick in the test substance compared to vehicle control (t-test, p <0.05).

Example 13 Analgesic activity of active compounds in chronic stenosis injury model (predictive example)
Peripheral nerve lesions can generate symptoms that include exaggerated responses to light touches (tactile allodynia) in addition to spontaneous pain. The chronic stenosis injury model is a neuropathic pain model.

  Has a body weight of 180 ± 20 g. Male Sprague Dawley rats are used. Under pentobarbital (50 mg / kg, 5 ml / kg, intraperitoneal) anesthesia, the sciatic nerve is exposed at the mid-thigh level. About 1 mm apart, a ligature thread (4-0 chrome gut) is tied loosely around the nerve. The animals are then individually housed in gauges with soft bedding for 7 days prior to testing. The contraction of the sciatic nerve produces nerve damage and unilateral neuropathic pain.

  On the day of the experiment, animals are kept away from food overnight before testing. Rats are placed under an inverted plexiglass cage on a wire mesh rack and allowed to acclimate for 20-30 minutes. Mechanical allodynia is assessed by the Chaplan up / down method using von Frey filament against the plantar surface of the left hind limb. See Chaplan, et al. J. Neuroscience Methods, 53: 55-63, 1994.

  Only if pain threshold at 7-14 days after nerve ligation (pretreatment) is reduced by 10g of force on individual limb response prior to nerve ligation (preligation), ie allodynia is clearly present Rats are preselected for experiments.

  An ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, is prepared according to Example 5 in a gel formulation.

  In gel formulation, active compound (1-5%), 1% Tween 80, active compound, morphine (positive control, oral, 20 mg / kg), topical vehicle (gel formulation without active compound), and oral Evaluate vehicle (1% Tween 80 in water).

  Either test substance or vehicle is administered orally (20-60 mg / kg) or topically (1-5% gel formulation) to the plantar surface of the left hind limb. Mechanical allodynia tests are performed 30 minutes before the single dose of the test substance or vehicle (pretreatment) and 1 and 3 hours after the single dose (posttreatment). Measure limb escape thresholds for control and test compounds.

Example 14 Treatment of knee pain (prediction example)
Objective: To investigate the efficacy of active compounds in gel formulations in patients with mild to moderate knee pain associated with osteoarthritis after suspension of standard NSAID treatment. The focus of this study is on the symptoms caused by painful arthritis. Clinical trials utilize the knee deformity as a well-established paradigm for other musculoskeletal disorders.

Formulation: A gel formulation (Example 4) containing the active compound ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide at 1% and 5% is used in this example. The placebo contains the same gel without the active compound.

Methodology: Randomized, double-blind, placebo-controlled, parallel processing, multicenter clinical activity study.
Patients with osteoarthritis with knee pain controlled by a stable dose of standard NSAID therapy for at least 2 months discontinue use of the NSAID for a 7-day drug holiday. The patient is then randomized to a 1: 1: 1 ratio (1% active gel, 5% active gel, placebo). A total of up to 150 patients will be enrolled and treated for 7 days at 8, 10, 14 and 21 days.

  An active gel or placebo is applied to the affected knee 3 times a day for 7 days for a total of 21 treatments every 4-6 hours while awake.

  Patients are treated for 7 days, followed by an additional 14 days. The NSAID will resume after the 10th day visit.

Evaluation criteria:
safety:
• Adverse events throughout the study (AE).
Physical examination at registration (−7 days, start of NSAID washout period), Baseline (Day 1, start of treatment), Day 10 and Day 21.
• Vital signs up to enrollment (day -7, start of NSAID washout period), baseline (day 1, start of treatment), and days 2, 4, 8, 10, 14, and 21.
• Baseline clinical laboratory measurements (day 1), days 8 and 14.

Clinical activity:
The primary clinical activity parameter is a measurement of pain at the site of application as quantified by the VAS and Western Ontario and McMaster University (WOMAC) scales. The effect of treatment on knee swelling, tenderness and inflammation is recorded, and the time to pain reduction or eradication after treatment is recorded.

Research endpoint:
The primary clinical activity endpoint is:
・ Changes from baseline (1st day) to 8th day in WOMAC dysfunction index:
-Pain (scale 0-20).
-Stiffness (scale 0-8).
-Physical function (scale 0-68).

Secondary clinical activity endpoints are:
Change from baseline (Day 1) to Day 8 on the VAS pain scale (1-100).
Diurnal changes in the VAS pain scale on days 2 and 3, as measured by changes from daily baseline (pretreatment 1) to 30 minutes after treatment 2.
Change in investigator assessment of swelling, tenderness and inflammation from baseline (Day 1) to 30 and 60 minutes after the first application on Day 1.
Change in investigator assessment of swelling, tenderness and inflammation from baseline (Day 1) to Day 8.
• Time to pain reduction or eradication following each topical application of active gel or placebo gel.
• Use of rescue medication (APAP).

Example 15. Treatment of atopic dermatitis (virtual example)
Objective: To investigate the effectiveness of active compounds in patients with atopic dermatitis.

Formulation: Prepare ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, in a gel formulation (according to Example 5). To do. The placebo contains the same gel without the active compound.

Methodology: This is a randomized, double-blind, placebo-controlled, parallel processing clinical activity study.

  Male and female patients with mild to severe atopic dermatitis are enrolled after all treatment interruptions for atopic dermatitis for 4 weeks prior to the start of the study. Patients are randomized at a 1: 1 ratio (active gel, placebo). A total of 300 patients will be enrolled and treated.

  Active gel or placebo is applied to the affected area of the body twice a day for 12 weeks. Treatment results are evaluated up to 12 weeks and then at 2 week intervals 4 weeks after discontinuation of study drug application.

Criteria for evaluation:
safety:
Erythema, safety by general medical history and physical signs, by laboratory tests for hematology, serum chemistry and urinalysis, and using a rating scale of “0” (pear) to “3” (severe), Evaluated by assessment of local application site tolerance parameters for scaling, dryness, tingling pain / burns.

Effectiveness:
Efficacy is assessed using:
1. Comprehensive assessment of disease severity at the start of the study and up to 12 weeks, and then at 2 week intervals 4 weeks after discontinuation of study medication. The investigator's overall rating (IGA) is a scale of 0-4 (0 = none or clear, 1 = nearly none, 2 = mild involvement, 3 = moderate disease involvement, and 4 = severe Disease involvement).

Each parameter evaluated on a scale of 2.0-4 (0 = none or clear, 1 = nearly none, 2 = mild involvement, 3 = moderate disease involvement, and 4 = severe disease involvement) Individual assessment of representative target atopic dermatitis areas of involvement for erythema, induration, lichenification, scaling and exudation and crusting.

  Individual statistical analyzes of these efficacy assessments are performed at each 2-week study time point. The final assessment of efficacy is based on a comparison of the active group to the vehicle group at the end of 12 weeks of treatment. The treatment assessment after 4 weeks is used to assess the endurance of the treatment effect after a medication interruption.

Example 16 Psoriasis treatment (virtual example)
Objective: To investigate the effectiveness of active compounds in patients with psoriasis vulgaris.

Formulation: Prepare ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, in a gel formulation (according to Example 5). To do. The placebo contains the same gel without the active compound.

Methodology: This is a randomized, double-blind, placebo-controlled, parallel processing clinical activity study.

  Male and female patients with mild to severe atopic dermatitis are enrolled. Patients discontinue all treatment for psoriasis vulgaris for 4 weeks prior to the start of the study. Patients are randomized at a 1: 1 ratio (active gel, placebo). A total of 200 patients will be enrolled and treated.

  Active gel or placebo is applied to the affected area of the body twice a day for 12 weeks. Treatment results are evaluated up to 12 weeks and then at 2 week intervals 4 weeks after discontinuation of study drug application.

Criteria for evaluation:
safety:
Erythema, safety by general medical history and physical signs, by laboratory tests for hematology, serum chemistry and urinalysis, and using a rating scale of “0” (pear) to “3” (severe), Evaluated by assessment of local application site tolerance parameters for scaling, dryness, tingling pain / burns.

Effectiveness:
Efficacy is assessed using:
1. Comprehensive assessment of disease severity at the start of the study and up to 12 weeks, and then at 2 week intervals 4 weeks after discontinuation of study medication. The investigator's overall rating (IGA) is a scale of 0-4 (0 = none or clear, 1 = nearly none, 2 = mild involvement, 3 = moderate disease involvement, and 4 = severe Disease involvement).

Each parameter evaluated on a scale of 2.0-4 (0 = none or clear, 1 = nearly none, 2 = mild involvement, 3 = moderate disease involvement, and 4 = severe disease involvement) Individual assessment of representative target psoriasis lesion areas for involvement in erythema, scaling and thickness.

  Statistical analysis of each efficacy assessment is performed for each 2-week study time point. The final assessment of efficacy is based on a comparison of the active group to the vehicle group at the end of treatment at 12 weeks. The treatment assessment after 4 weeks is used to assess the endurance of the treatment effect after a medication interruption.

Example 17. Treatment of acne (virtual example)
Objective: To investigate the effectiveness of active compounds in patients with acne vulgaris.

Formulation: Prepare ω- (methylsulfonyl) alkylamine or ω- (methylsulfonyl) alkylamide, such as 3- (methylsulfonyl) propylamine and 3- (methylsulfonyl) propionamide, in a gel formulation (according to Example 5). To do. The placebo contains the same gel without the active compound.

Methodology: This is a randomized, double-blind, placebo-controlled, parallel processing clinical activity study.

  Male and female patients with mild to severe acne vulgaris are enrolled. Patients discontinue all treatment for psoriasis vulgaris for 4 weeks prior to the start of the study. Patients are randomized at a 1: 1 ratio (active gel, placebo). A total of 500 patients will be enrolled and treated.

  Active gel or placebo is applied to the affected area of the body twice a day for 12 weeks. Treatment results are evaluated up to 12 weeks and then at 2 week intervals 4 weeks after discontinuation of study drug application.

Criteria for evaluation:
safety:
Erythema, safety by general medical history and physical signs, by laboratory tests for hematology, serum chemistry and urinalysis, and using a rating scale of “0” (pear) to “3” (severe), Evaluated by assessment of local application site tolerance parameters for scaling, dryness, tingling pain / burns.

Effectiveness:
Efficacy is assessed using:
1. Comprehensive assessment of disease severity at the start of the study and up to 12 weeks, and then at 2 week intervals 4 weeks after discontinuation of study medication. The investigator's overall rating (IGA) is a scale of 0-4 (0 = none or clear, 1 = nearly none, 2 = mild involvement, 3 = moderate disease involvement, and 4 = severe Disease involvement).

2. Individual assessment of all types of acne lesions: open and closed comedones, papules, pustules, nodules and cysts.

  Statistical analysis of each efficacy assessment is performed for each 2-week study time point. The final assessment of efficacy is based on a comparison of the active group to the vehicle group at the end of treatment at 12 weeks. The treatment assessment after 4 weeks is used to assess the endurance of the treatment effect after a medication interruption.

  The foregoing describes preferred embodiments of the present invention, and it is to be understood that modifications may be made without departing from the scope of the invention as set forth in the claims.

Claims (18)

A pharmaceutically acceptable carrier, and a compound of A or B,

Or a pharmaceutically acceptable salt thereof,
A pharmaceutical composition comprising:   The pharmaceutical composition according to claim 1, wherein the compound has a purity of at least 90% (w / w) and the composition is a topical form of a gel, cream, lotion, ointment or patch.   The pharmaceutically acceptable carrier is a softening agent selected from the group consisting of lauryl lactate, diethylene glycol monoethyl ether, tricaprylic / capric glycerides, octisalate, silicone oil, squalene, and sunflower oil. 2. The pharmaceutical composition according to 2.   The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable carrier is a penetration enhancer selected from the group consisting of lactate ester and diethylene glycol monoethyl ether.   The pharmaceutical composition according to claim 4, further comprising acrylate / C10-30 alkyl and tris (2-hydroxyethyl) amine.   The pharmaceutical composition according to claim 1, wherein the compound has a purity of at least 90% (w / w) and the composition is in the oral form of a tablet or capsule.   The pharmaceutical composition according to claim 1 for treating inflammation or pain in a subject.   8. A pharmaceutical composition according to claim 7, for reducing or alleviating signs of localized symptoms of inflammation characterized by acute or chronic swelling, pain, or redness.   The pharmaceutical composition according to claim 7, which is a topical preparation.   The pharmaceutical composition according to claim 7, which is an oral preparation.   The inflammation and / or pain is musculoskeletal sprain, musculoskeletal strain, tendonopathy, peripheral nerve root disorder, osteoarthritis, degenerative joint disease, juvenile arthritis, gout, ankylosing spondylitis, psoriatic arthritis 8. A skeletal or muscular disease or condition selected from the group consisting of: system lupus lupus erythematosus, chondritis, tendonitis, bursitis, temporomandibular syndrome, and fibromyalgia. Pharmaceutical composition.   8. The pharmaceutical composition of claim 7, wherein the inflammation and / or pain is associated with a joint, ligament, tendon, bone, muscle, or fascia.   8. A pharmaceutical composition according to claim 7, wherein the inflammation and / or pain is associated with dermatitis or psoriasis.   The pharmaceutical composition according to claim 13, wherein the dermatitis is atopic dermatitis or contact dermatitis.   A pharmaceutical composition according to claim 1 for the treatment of inflammatory skin disease or skin disorder, wherein the inflammatory skin disease or skin disorder is dermatitis, psoriasis or acne.   16. To treat atopic dermatitis and to alleviate one or more symptoms selected from the group consisting of erythema, induration, lichenification, scaling, exudation and crusts The pharmaceutical composition as described.   16. A pharmaceutical composition according to claim 15 for treating psoriasis and for alleviating one or more symptoms selected from the group consisting of erythema, scaling and / or thickness of psoriasis lesions. .   16. A pharmaceutical composition according to claim 15 for treating acne and for alleviating acne lesions selected from the group consisting of closed faced blisters, papules, pustules, nodules and cysts.